6WQ7

Carbonic Anhydrase II Complexed with 2-((3-Aminopropyl)(phenethyl)amino)-N-(4-fluorobenzyl)-N-(4-sulfamoylphenethyl)acetamide

6WQ7 の概要

• エントリーDOI: 10.2210/pdb6wq7/pdb
• 分子名称: Carbonic anhydrase 2, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ZINC ION, ... (5 entities in total)
• 機能のキーワード: inhibitor, sulfonamide, caii, ca ii, lyase, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30003.28

構造登録者

Andring, J.T.,Combs, J.E.,Lomelino, C.,McKenna, R. (登録日: 2020-04-28, 公開日: 2020-06-24, 最終更新日: 2023-10-18)

主引用文献

Bonardi, A.,Nocentini, A.,Bua, S.,Combs, J.,Lomelino, C.,Andring, J.,Lucarini, L.,Sgambellone, S.,Masini, E.,McKenna, R.,Gratteri, P.,Supuran, C.T.
Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action.
J.Med.Chem., 63:7422-7444, 2020

PubMed Abstract: The "tail approach" has become a milestone in human carbonic anhydrase inhibitor (hCAI) design for various therapeutics, including antiglaucoma agents. Besides the classical hydrophobic/hydrophilic division of hCAs active site, several subpockets have been identified at the middle/outer active sites rim, which could be targeted to increase the CAI isoform selectivity. This postulate is explored here by three-tailed benzenesulfonamide CAIs () to fully exploit such amino acid differences among hCAs. In this proof-of-concept study, an extensive structure-activity relationship (SAR) study was carried out with 32 such benzenesulfonamides differing in tails combination that were assayed for hCAs I, II, IV, and XII inhibition. A structural study was undertaken by X-ray crystallography and tools to assess the ligand/target interaction mode. The most active and selective inhibitors against isoforms implicated in glaucoma were assessed in a rabbit model of the disease achieving an intraocular pressure-lowering action comparable to the clinically used dorzolamide.

PubMed: 32519851
DOI: 10.1021/acs.jmedchem.0c00733

実験手法

X-RAY DIFFRACTION (1.304 Å)